This invention is in the area of controlled delivery devices for the administration of anesthetics.
Products for the moderation of pain, referred to as analgesics, represent one of the largest markets targeted by pharmaceutical companies. In fact, the market for ethical analgesic products in the United States alone is estimated to reach three billion dollars in 1990 and rise to over four billion dollars by 1995.
Pharmaceutical analgesics include a variety of classes of drugs, such as general anesthetics, non-steroidal anti-inflammatories, and local anesthetics. General anesthetics reduce pain by producing a loss of consciousness. Local anesthetics cause a loss of sensation in a localized area of the body without a loss of consciousness. Non-steroidal anti-inflammatories may ameliorate the pain but do not cause a loss of sensation or consciousness.
Among the general anesthetics are centrally acting narcotics, including morphine, demerol, fentanyl and codeine. These drugs act through opiate receptors in the central nervous system. The major advantage of centrally acting narcotics is the production of profound widespread analgesia for severe pain. These opiates are administered internally, parenterally, or topically. Dosage forms are available that are effective for durations of from 4 to 12 hours. Although centrally acting narcotics are quite effective in mitigating pain, they are associated with serious side effects, including addiction, respiratory depression, apnea, circulatory depression, respiratory arrest, shock and cardiac arrest.
Non-steroidal anti-inflammatory drugs (NSAIDs) include ibuprofen, indomethacin, acetaminophen, piroxicam, naproxen, flufenamic acid and mefenamic acid. The NSAIDs are generally administered orally two to four times daily. They are less potent than the centrally acting narcotics and have a different spectrum of side effects. The major adverse reactions of NSAIDs include gastrointestinal tract ulceration, bleeding and perforation, blurred and/or diminished vision, edema, and prolonged bleeding time.
Local anesthetics block the generation and conduction of nerve impulses by increasing the threshold for electrical excitation in the appropriate nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. Local anesthetics are extremely potent and result in a virtually complete loss of sensation in the treated area of the body. Loss of nerve function is generally observed in the following order: pain, temperature, touch, proprioception, and skeletal muscle tone. Commonly used anesthetics include carbocaine, xylocaine, and marcaine.
Local anesthetics are preferred over general anesthetics because of the serious complications that can occur during general anesthesia. However, even local anesthetics, which are usually injected as an aqueous solution, are eventually absorbed from the site of application into the circulation system, and their therapeutic indices, dosages, and frequency of dosage, must therefore be strongly considered before administration to a patient. The more frequently the local anesthetic must be administered, the more likely it is that systemic toxicity will develop.
A local anesthetic must remain active long enough to allow sufficient time for surgery or pain moderation. However, its effectiveness should not last so long that it creates an extended recovery period. There are situations in which local anesthesia lasting for a few days, weeks or even months is desirable. In general, the duration of action of the local anesthetic is proportional to the time during which it has contact with the nerve tissue. Therefore, procedures that maintain the localization of the drug at the nerve greatly prolong the period of anesthesia.
To be efficacious, local anesthetics must have hydrophobic qualities to bind to and cross the cell membrane, yet also have hydrophilic properties to dissolve in water and diffuse to the site of action. The duration of action, which is limited by the fairly rapid process of absorption into the blood, can be increased by decreasing the water solubility of the drug, however, this also decreases the ability to administer the drug in an aqueous injection.
Local anesthetics have been prepared in a number of delivery systems. U.S. Pat. Nos. 4,622,219 and 4,725,442 to Haynes describe a method to administer a liquid general anesthetic such as halothane, isoflurane, enflurane, or methoxyflurane as a local anesthetic, by incorporating the liquid into an unilamellar phospholipid vesicle that consists of a spherical lipid layer surrounding an internal oil phase. U.S. Pat. No. 4,761,288 to Messi describes a multiphase drug delivery system that includes lipid vesicles encapsulating a saturated solution of biologically active compound and biologically active compound in the solid form. European Patent Application No. 88300529.0 filed by Vestar, Inc., describes aqueous emulsions of phospholipid resides at 100 nm or less diameters encapsulating active ingredients and a triglyceride.
Liposomes have also been used for encapsulation of anesthetics. The problems with using liposomes and vesicles as delivery devices are manifold. They are difficult to prepare, unstable, and can only be used for encapsulation of certain types of materials.
It is therefore an object of the present invention to provide a composition and method to locally alleviate pain for an extended period without the need for frequent administration of the drug.
It is a further object of the present invention to provide a composition and method to locally alleviate pain for an extended period without the side effects associated with general anesthetic.
It is another object of the present invention to provide a composition, and method of use thereof, for alleviation of pain, that is easy to prepare and stable for an extended period of time prior to use and in vivo.